Epigenetic regulation of inflammatory genes involving histone methylation is associated with hyperimmune response in COVID-19 patients

Abstract

Abstract One of the leading causes of the severe COVID-19 disease symptoms is the production of massive amounts of pro-inflammatory cytokines. Although the precise mechanisms that trigger such hyperimmune response is unclear, epigenetic mechanisms are known to play important roles in the regulation of cytokine production and inflammation. In this study we examined global gene expression and histone methylation profile in the PBMCs of hospitalized COVID-19 patients. Despite individual variations, the expressions of many inflammation-related genes such as Arginase 1 (ARG1) and IL1 receptor 2 (IL1R2) were significantly upregulated in COVID-19 patients. We also found the expressions of coagulation-related genes, VWF and Protein S, were altered in COVID-19 patients. The expression patterns of some genes such as IL1R2 correlated with their histone methylation marks. Pathway analysis revealed that most of these dysregulated genes were in the TGFb, IL1b, IL6 and IL17 pathway. Interestingly, we found that the majority of those altered genes were in the dexamethasone targeting pathway. We also found that the expression of BMX, a member of TEC family kinases, was significantly increased in the PBMCs of COVID-19 patient at both RNA level and protein level. Interestingly, some TEC kinase inhibitors have been used to treat COVID-19 patients in clinical trials. Overall, this study has identified genes in PBMCs of COVID-19 patients with altered histone mark and gene expression profile, providing important information towards identifying potential biomarkers and therapeutic targets for COVID-19 disease. (Supported by NIH grants P01AT003961, P20GM103641, R01AT006888, R01ES030144, R01AI129788 and R01AI123947 to P.S.N and M.N.) Supported by NIH grants P01AT003961, P20GM103641, R01AT006888, R01ES030144, R01AI129788 and R01AI123947 to P.S.N and M.N.